| Structural highlights
Disease
[SH2B1_HUMAN] Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency;Proximal 16p11.2 microdeletion syndrome;Distal 16p11.2 microdeletion syndrome.
Function
[SH2B1_HUMAN] Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on tyrosine residues. These phosphotyrosines form potential binding sites for other signaling proteins. GH also promotes serine/threonine phosphorylation of SH2B1 and these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP) signaling, binds to and potentiates the activation of JAK2 by globally enhancing downstream pathways. In response to leptin, binds simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-kinase pathway. Acts as positive regulator of NGF-mediated activation of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2 and of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2, the mechanism seems to involve dimerization of both, SH2B1 and JAK2. Enhances RET phosphorylation and kinase activity. Isoforms seem to be differentially involved in IGF-I and PDGF-induced mitogenesis (By similarity).[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
SH2B1 is a multidomain protein that serves as a key adapter to regulate numerous cellular events, such as insulin, leptin, and growth hormone signaling pathways. Many of these protein-protein interactions are mediated by the SH2 domain of SH2B1, which recognizes ligands containing a phosphorylated tyrosine (pY), including peptides derived from janus kinase 2, insulin receptor, and insulin receptor substrate-1 and -2. Specificity for the SH2 domain of SH2B1 is conferred in these ligands either a hydrophobic or an acidic side chain at the +3 position C-terminal to the pY. This specificity for chemically disparate species suggests that SH2B1 relies on distinct thermodynamic or structural mechanisms to bind to peptides. Using binding and structural strategies, we have identified unique thermodynamic signatures for each peptide binding mode, and several SH2B1 residues, including K575 and R578, that play distinct roles in peptide binding. The high-resolution structure of the SH2 domain of SH2B1 further reveals conformationally plastic protein loops that may contribute to the ability of the protein to recognize dissimilar ligands. Together, numerous hydrophobic and electrostatic interactions, in addition to backbone conformational flexibility, permit the recognition of diverse peptides by SH2B1. An understanding of this expanded peptide recognition will allow for the identification of novel physiologically relevant SH2B1/peptide interactions, which can contribute to the design of obesity and diabetes pharmaceuticals to target the ligand-binding interface of SH2B1 with high specificity. This article is protected by copyright. All rights reserved.
Diversity in Peptide Recognition by the SH2 Domain of SH2B1.,McKercher MA, Guan X, Tan Z, Wuttke DS Proteins. 2017 Nov 11. doi: 10.1002/prot.25420. PMID:29127727[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kong M, Wang CS, Donoghue DJ. Interaction of fibroblast growth factor receptor 3 and the adapter protein SH2-B. A role in STAT5 activation. J Biol Chem. 2002 May 3;277(18):15962-70. Epub 2002 Feb 4. PMID:11827956 doi:http://dx.doi.org/10.1074/jbc.M102777200
- ↑ Wang X, Chen L, Maures TJ, Herrington J, Carter-Su C. SH2-B is a positive regulator of nerve growth factor-mediated activation of the Akt/Forkhead pathway in PC12 cells. J Biol Chem. 2004 Jan 2;279(1):133-41. Epub 2003 Oct 16. PMID:14565960 doi:http://dx.doi.org/10.1074/jbc.M310040200
- ↑ Nishi M, Werner ED, Oh BC, Frantz JD, Dhe-Paganon S, Hansen L, Lee J, Shoelson SE. Kinase activation through dimerization by human SH2-B. Mol Cell Biol. 2005 Apr;25(7):2607-21. PMID:15767667 doi:http://dx.doi.org/10.1128/MCB.25.7.2607-2621.2005
- ↑ Zhang Y, Zhu W, Wang YG, Liu XJ, Jiao L, Liu X, Zhang ZH, Lu CL, He C. Interaction of SH2-Bbeta with RET is involved in signaling of GDNF-induced neurite outgrowth. J Cell Sci. 2006 Apr 15;119(Pt 8):1666-76. Epub 2006 Mar 28. PMID:16569669 doi:http://dx.doi.org/jcs.02845
- ↑ Donatello S, Fiorino A, Degl'Innocenti D, Alberti L, Miranda C, Gorla L, Bongarzone I, Rizzetti MG, Pierotti MA, Borrello MG. SH2B1beta adaptor is a key enhancer of RET tyrosine kinase signaling. Oncogene. 2007 Oct 4;26(45):6546-59. Epub 2007 Apr 30. PMID:17471236 doi:http://dx.doi.org/10.1038/sj.onc.1210480
- ↑ Rui L, Carter-Su C. Platelet-derived growth factor (PDGF) stimulates the association of SH2-Bbeta with PDGF receptor and phosphorylation of SH2-Bbeta. J Biol Chem. 1998 Aug 14;273(33):21239-45. PMID:9694882
- ↑ Kotani K, Wilden P, Pillay TS. SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase. Biochem J. 1998 Oct 1;335 ( Pt 1):103-9. PMID:9742218
- ↑ McKercher MA, Guan X, Tan Z, Wuttke DS. Diversity in Peptide Recognition by the SH2 Domain of SH2B1. Proteins. 2017 Nov 11. doi: 10.1002/prot.25420. PMID:29127727 doi:http://dx.doi.org/10.1002/prot.25420
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